Extracranial Neuromodulation

Motor Thresholds

Motor threshold (MT) represents the minimal stimulation intensity producing MEPs in the target muscle. This can be measured in resting (resting motor threshold [RMT]) or contracting (active motor threshold [AMT]) muscles. RMT is determined to the nearest 1% of the maximum stimulator output and is commonly defined as the minimal stimulus intensity required to produce MEPs of greater than 50 μV in at least 5 out of 10 consecutive trials. Here the MEP amplitudes are usually measured peak to peak. AMT is determined in the moderately active muscle (usually between 5% and 10% of the maximal voluntary contraction) and is defined as the minimum intensity that produces either MEPs of greater than 100 μV or silent period (SP) or MEPs of greater than 200 μV in at least 5 out of 10 consecutive trials. Other methods are also used for MT and the adaptive method may be the most accurate ( ). MT in resting muscle reflects the excitability of a central core of neurons, depending on the excitability of individual neurons and their local density. Since MT can be influenced by drugs that affect voltage-gated sodium and calcium channels, it may represent membrane excitability.

Motor Evoked Potential Recruitment Curve (Stimulus Response Curve; Input-Output Curve)

The recruitment curve is the growth of MEP size as a function of stimulus intensity ( ). The underlying physiology is poorly understood, but appears to involve neurons in addition to the core region activated at threshold. The slope of the recruitment curve is related to the number of corticospinal neurons that can be activated at a given stimulus intensity, mainly indirectly through corticocortical connections. The neurons that can be activated at a lower threshold are highly excitable neurons located in core regions of corresponding motor cortex, while neurons recruited at a higher intensity may have a higher threshold for activation, either because they are intrinsically less excitable or because they are spatially further from the magnetic stimulus’s center of activation. These neurons would be part of the “subliminal fringe.” The changes in recruitment curve are usually more prominent with higher-intensity stimulations. This finding suggests that recruitment curve may represent the excitability of less excitable or peripherally located neurons, rather than highly excitable core neurons, or the connections between them. The slope of recruitment curve is increased by drugs that enhance adrenergic transmission, such as dextroamphetamine, and is decreased by sodium and calcium channel blockers and by gamma-aminobutyric acid (GABA) agonists.

Silent Period and Long-Interval Intracortical Inhibition

The SP is a pause in ongoing voluntary electromyography (EMG) activity produced by TMS ( Fig. 37.1 , A ). The SP is usually measured with a suprathreshold stimulus in moderately active muscle (usually 5%–10% of maximal voluntary contraction). SP duration is usually defined as the interval between the magnetic stimulus and the first reoccurrence of rectified voluntary EMG activity ( ). While the first part of the SP is due in part to spinal-cord refractoriness, the latter part is entirely due to cortical inhibition (cortical silent period [CSP]). If a second suprathreshold test stimulation (TS) is given during the SP following suprathreshold conditioning stimulus (CS; usually 50–200 ms after the first stimulus), its MEP is significantly suppressed (long intracortical inhibition [LICI]; Fig. 37.1 , B ; ). SP and LICI appear to assess GABA _B function, although other drugs affecting membrane excitability or dopaminergic transmission also influence SP. Although LICI and SP share similar mechanisms, they may not be identical because they are affected differently in various diseases ( ).

Short-Interval Intracortical Inhibition and Intracortical Facilitation

Various inhibitory and excitatory connections in the motor cortex can be evaluated by TMS using a paired-pulse technique. A subthreshold CS preferentially excites interneurons, by which MEPs from a following TS are suppressed at interstimulus intervals (ISIs) of 1–5 ms (intracortical inhibition; SICI for such inhibition at short intervals) or facilitated at ISIs of 8–20 ms (ICF; Fig. 37.2 ; ). SICI and ICF reflect interneuronal activity in the cortex. SICI is likely largely a GABAergic effect, especially related to GABA _A receptors. ICF is largely a glutamatergic effect. However, subcortical or even spinal activation may also be involved in ICF, as ICF is not related to changes in I-waves ( ). SICI can be divided into two phases, with maximum inhibition at ISIs of 1 ms and 2.5 ms. SICI at 1 ms ISI is presumably caused either by neuronal refractoriness resulting in desynchronization of the corticospinal volley or by different inhibitory circuits, while SICI at ISI of 2 ms or longer is most likely a synaptic inhibition.

The magnitude of SICI depends on the intensity of CS and TS. With a given CS, TS intensity variation results in a U-shaped variation of SICI magnitude with a maximum inhibition at TS producing MEPs with peak-to-peak amplitude of around 1 mV. Variation of CS intensity at a given TS intensity also leads to a U-shaped change in SICI magnitude, with maximum SICI occurring at CS intensity around 90% AMT or 70% RMT. The low end of CS intensity producing SICI represents SICI threshold. Increased magnitude of SICI with CS above SICI threshold may indicate increasing recruitment of inhibitory interneurons that contribute to SICI, while decreased magnitude of SICI with increased CS intensities above those producing maximum SICI may represent recruitment of facilitatory processes (presumably, those mediating short-interval intracortical facilitation [SICF]; see next section) that superimpose with SICI.

Short-Interval Intracortical Facilitation

SICF is also known as facilitatory I-wave interactions; it is also measured in a paired-pulse TMS protocol. In contrast to SICI and ICF, however, SICF is elicited by a suprathreshold first stimulus and a subthreshold second stimulus, or two near-threshold stimuli. SICF is usually observed at discrete ISIs of 1.1–1.5 ms, 2.3–2.9 ms, and 4.1–4.4 ms. ISIs producing facilitatory response in SICF are about 1.5 ms apart, similar to the intervals of different I-waves, which suggests that SICF originates in those neural structures responsible for the generation of I-waves ( ). The second pulse is thought to excite the initial axon segments of excitatory interneurons, which are depolarized by excitatory postsynaptic potentials from the first pulse without firing an action potential. In addition, it is important to mention that the final outcome measured as MEP induced by a paired-pulse TMS reflects a complex interplay between cortical inhibition and facilitation, because the stimulus parameters (stimulus intensities for the first and second stimuli and ISI between two stimuli) for testing SICI and SICF overlap ( ). Indeed, GABA _A agonists reduce both SICI and SICF. Therefore, reduced SICI observed in various disease conditions may represent either a true reduction in SICI or enhanced facilitation, or both. Measuring the low and high ends of CS producing SICI is now considered to be a more sensitive and informative method to assess neurophysiological changes occurring in various conditions than simply measuring the magnitude of SICI.

Short-Latency and Long-Latency Afferent Inhibition

Afferent inhibition can be measured by applying a conditioning sensory stimulus such as median nerve stimulation followed by a test stimulus over the contralateral motor cortex. MEP inhibition occurs usually at ISIs of approximately 20 ms (short-latency afferent inhibition [SAI]) and 200 ms (long-latency afferent inhibition [LAI]; ). SAI is thought to be of cortical origin because the recordings of corticospinal volleys demonstrate a strong suppression of later I-waves with unaffected earlier descending waves. SAI is reduced by the acetylcholine antagonist scopolamine, suggesting that SAI can be used to test the integrity of cholinergic neural circuits. Accordingly, SAI is reduced in patients with Alzheimer disease (AD), and is improved with a single dose of rivastigmine, an acetylcholinesterase inhibitor. The mechanism mediating LAI is still unclear, but is thought to be different from that of SAI.

Surround Inhibition

Surround inhibition (SI), suppression of excitability in an area surrounding an activated neural network, has been proposed to be an essential mechanism in the motor system where it could aid the selective execution of desired movements. Using a self-triggered TMS technique, in which TMS is set to be triggered by the EMG activity from the activated muscle (agonist), MEPs of the surround muscles (i.e., the muscles near to the agonist but unrelated to its movement) are suppressed during the movement (up to 80 ms after the EMG onset) despite enhanced spinal excitability ( ). SI is reduced in patients with focal hand dystonia and may be altered in other disorders of human motor control, such as Parkinson disease (PD).

Other Inhibitory Phenomena of the Motor Cortex

Interhemispheric inhibition (IHI) can also be assessed by TMS, by applying a CS to the motor cortex, which suppresses MEPs produced by a test stimulus over the contralateral motor cortex at ISIs of between 6 ms and 50 ms ( ). IHI is mediated by transcallosal fibers at the cortical level, although subcortical structures may also be involved ( ). Long-latency IHI at ISIs between 20 and 50 ms is likely mediated by GABA _B receptors.

Magnetic stimulation of the cerebellum, which can be performed using a double-cone coil, inhibits the MEPs produced by stimulation of the contralateral motor cortex 5–7 ms later (cerebellar inhibition, CBI; ). Cerebellar stimulation is thought to activate Purkinje cells in the cerebellar cortex, leading to inhibition of the deep cerebellar nuclei (such as the dentate nucleus) which have a dyssynaptic excitatory pathway to the motor cortex via the ventral thalamus. CBI is reduced or absent in patients with cerebellar degeneration or lesions in the cerebellothalamocortical pathway.

Table 37.1 summarizes the characteristics of different motor excitability measures using TMS.

Interaction Between Different Cortical Circuits

The cortical circuits in the M1 are not independent of each other but are interconnected within a complex neural network. The interaction between two cortical circuits can be expressed as the changes in one circuit at the presence of the other and can be tested with a triple-pulse TMS paradigm (review see ). Notably, it was well demonstrated that SICI decreases when LICI is present ( ), and the disinhibitory effect can be blocked by a GABA _B antagonist ( ), indicating that LICI inhibits SICI at a presynaptic level.